Chalcones, considered as the precursor of flavonoids and isoflavonoids, are abundant in edible plants. Chalcone derivatives as an ingredient of yellow pigments in plants influence the colors of the plants and protect the plants from ultraviolet rays as well. The chalcone derivatives are abundant in Coreopsis, one of the compositae plants. Representative chalcones include 2′,6′-dihydroxy-4′-metoxychalcone, carthamin, etc., which are contained in the plants such as cinnamon, safflower, pepper, etc. Dihydrochalcones are contained primarily in rosaceae and ericaceae plants. One of the dihydrochalcones such as phloridzin, which is in the apples is related to the resistibility for diseases of the apples. It has been well known that such chalcone derivatives display a diverse array of pharmacological activities, such as anti-protozoal (Liu, M. et. al., J. Med. Chem. 2001, 44, 4443), anti-inflammatory (Babu, M. A., et. al., Bioorg. Med. Chem. 2003, 10, 4035), immuno-modulatory (Barfod, L., et. al., Int. Immunopharmacol. 2002, 2, 545), nitric oxide inhibitory (Rojas, J., et. al., Bioorg. Med. Chem. Lett. 2002, 12, 1951), anticancer (Kumar, S. K., et. al., J. Med. Chem. 2003, 46, 2813), anti-HIV activities (Artico, M., et. al., J. Med. Chem. 1998, 41, 3984), etc.
Meanwhile, glycosidases are enzymes that hydrolyze sugar chains in the process of metabolisms of carbohydrate and glycoprotein to be degraded into monosaccharides or the other absorbable polysaccharides. These glycosidases are responsible for the processing and synthesis of complex carbohydrates, which are essential in numerous biological recognition processes (Bertozzi, C. R. et. al, Science 2001, 291, 2357; Morenem, K. W. et. al., Glycobiology 1994, 4, 113).
Recently, various attempts to try to screen glycosidase inhibitors have been made actively. For example, it has been reported that glycosidase inhibitors may be used as antidiabetic agents or antiobestic agents, since a variety of glycosidases participate in the food digestive system by degrading polysaccharides, such as starch, sucrose and the like, and oligosaccharides (Diabetes 1991, 40, 825-830).
Moreover, glycosidase inhibitors competitively inhibit the formation of glycosidases that participate in the process of forming mature glycoproteins from lipid-linked oligosaccharide intermediate. Accordingly, while the glycoproteins pass through endoplasmic reticulum to Golgi bodies, glycosidase inhibitors control the metabolism of such enzymes for sugar moieties of glycoproteins, thus inhibiting the formation of normal glycoproteins in cells (Nat. Rev. Drug Discov. 2002, 1, 65-75). As a result, signal transductions in cells, between cells and between tissues are disturbed to accumulate immature glycoproteins, thus inhibiting virus to couple with receptors of host cells and suppressing the formation of syncytiums required for the osmosis of host cell and virus. Consequently, the breeding of virus is inhibited. It has been reported that glycosidase inhibitors may be effectively used as anti-cancer agents (Cancer Res. 1991, 51, 718-723) and anti-viral agents (FEBS Lett. 1998, 430, 17-22).
Glycosidase inhibitors developed in the prior art include aza sugars (Kato, A. et al., J. Med. Chem. 2005, 48, 2036), isoxazoles (Schaller, C. et al., Bioorg. Med. Chem. Lett. 1999, 9, 277) and aminosugars (Chen, X. et al., Chem. Rev. 2003, 103, 1955). However, most of such glycosidase inhibitors are sugar mimics, of which syntheses require tedious multi-steps from carbohydrate or non-carbohydrate.
Meanwhile, it has been known that some of the chalcone based compounds described above have tyrosinase inhibitory activities (N. Ohad. et. al., J. Agric. Food Chem. 2003, 51, 1201). Tyrosinase (EC. 1. 14. 18. 1) is known to be the most important enzyme in melanin biosynthesis occurring in the cells of plants, microorganisms and mammals. This enzyme converts tyrosine to dihydroxyphenylalanine (DOPA), which is then converted to dopaquinone. This dopaquinone in turn can be readily converted to dopachrome, which is consequently converted to the black or brown melanins (G. Prota, 1992, Melanins and Melanogenesis). Such melanins existing in skin play an important role of protecting the body from ultraviolet rays and the like. However, an overproduction of melanin causes liver spots, freckles, etc., which accelerates skin aging, and is known to be one of the factors causing skin cancer. Accordingly, melanin synthesis inhibitors have been utilized as materials of skin-whitening cosmetics and agents for treating localized hyper-pigmentation (K, Maeda, J. Soc. Comet. Chem., 1991, 42, 361).
In the prior art, p-methoxyphenol, hydroquinone, kojic acid or arbutin were used as melanin synthesis inhibitors. However, their melanin inhibitory activities are weak or such inhibitors may cause side effects in that they damage the intrinsic functions of cells by denaturalizing pigment cells.
Moreover, with the object of inhibiting the melanin synthesis, vitamin C and its derivatives have been used. However, their tyrosinase inhibitory activities are also very low. Accordingly, new inhibitors for inhibiting tyrosinase activities and melanin syntheses even with a small dose and having a low cytotoxicity must be developed without delay (Chen, J., J. Agric. Food., 1991, 39).
The inventors of the present invention paying attention to the fact that there have been no researches on the chalcone derivatives, although the chalcone derivatives described above have excellent pharmacological activities, have synthesized a variety of novel chalcone derivatives having glycosidase inhibitory activities. Furthermore, the inventors of the present invention discovering that the chalcone derivatives of the present invention have tyrosinase and melanin synthesis inhibitory activities have completed the present invention by demonstrating that such derivatives can be used as a skin-whitening composition.